TWI496781B - Process for preparing methyl {4,6-diamino-2-(1-(2-fluorobenzyl)-1h-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl}methylcarbamate and its purification for use as pharmaceutically active compound - Google Patents
Process for preparing methyl {4,6-diamino-2-(1-(2-fluorobenzyl)-1h-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl}methylcarbamate and its purification for use as pharmaceutically active compound Download PDFInfo
- Publication number
- TWI496781B TWI496781B TW099140893A TW99140893A TWI496781B TW I496781 B TWI496781 B TW I496781B TW 099140893 A TW099140893 A TW 099140893A TW 99140893 A TW99140893 A TW 99140893A TW I496781 B TWI496781 B TW I496781B
- Authority
- TW
- Taiwan
- Prior art keywords
- formula
- methyl
- fluorobenzyl
- pyridin
- product
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C325/00—Thioaldehydes; Thioketones; Thioquinones; Oxides thereof
- C07C325/02—Thioketones; Oxides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Description
本發明係關於一種製備式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法。The present invention relates to a process for preparing {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3- of formula (I) A method of methyl pyrimidine-5-yl}methylaminocarbamate.
本發明另關於一種用於純化使用作為醫藥活性化合物之式(I)化合物粗產物之方法，其中為了純化，以中間物形式分離出{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(1：1)，即式(II)化合物The invention further relates to a process for the purification of a crude product of the compound of the formula (I) as a pharmaceutically active compound, wherein for purification, the {4,6-diamino-2-[1-(2) is isolated as an intermediate -fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamic acid methyl sulfinyl dimethane (1:1), Compound of formula (II)
或於此純化製程中以中間物形式產生，若適當，以混合物形式存在。Or in the form of an intermediate in the purification process, if appropriate, in the form of a mixture.
式(I)化合物係用作可溶鳥苷酸環化酶之激活劑，並可使用作為預防及/或治療心血管疾病之藥劑，例如用於治療高血壓及心衰竭、穩定型及不穩定型心絞痛、周邊及心臟血管疾病、心律不整、用於治療血栓栓塞疾病及局部缺血如心肌梗塞、中風、暫時性腦缺血、末梢血流失調、預防術後再狹窄如血栓溶解後血管成形術、經皮腔內血管成形術(PTA)、冠狀動脈氣球擴張術(PTCA)、繞道及用於治療動脈硬化、氣喘症及尿殖系統疾病如(例如)***肥大、***障礙、女性性功能障礙、骨鬆症、青光眼、肺性高血壓、胃輕癱及失禁。The compound of the formula (I) is used as an activator of soluble guanylate cyclase and can be used as an agent for preventing and/or treating cardiovascular diseases, for example, for treating hypertension and heart failure, stabilizing and unstable Angina pectoris, peripheral and cardiovascular diseases, arrhythmia, treatment of thromboembolic diseases and ischemia such as myocardial infarction, stroke, transient cerebral ischemia, peripheral blood loss, prevention of postoperative restenosis such as thrombosis after angioplasty Percutaneous transluminal angioplasty (PTA), coronary balloon dilatation (PTCA), bypass and for the treatment of arteriosclerosis, asthma and urinary system diseases such as, for example, prostatic hypertrophy, erectile dysfunction, female sexual function Disorders, osteoporosis, glaucoma, pulmonary hypertension, gastroparesis and incontinence.
式(I)化合物之製備及其純化原則上係已知的。WO 03/095451描述藉由下列途徑製備式(I)化合物。The preparation of the compounds of formula (I) and their purification are known in principle. WO 03/095451 describes the preparation of compounds of formula (I) by the following route.
在此，起初藉由催化氫化作用***出式(III)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-[(E)-苯基二氮烯基]嘧啶-4,6-二胺，並以式(IV)之2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺三鹽酸鹽形式分離出所得三胺基化合物。然後此三鹽酸鹽與式(V)之氯甲酸甲酯在溶劑吡啶中反應，以獲得式(VI)之4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基胺基甲酸甲酯。或者，ChemMedChem 2009,4,853-865描述該三胺基化合物係以三鹽酸鹽形式分離出，然後藉以NaHCO3 水溶液萃取產生HCl-游離鹼，且該游離鹼與式(V)之氯甲酸甲酯在溶劑吡啶中反應以獲得式(VI)化合物。式(VI)化合物然後與式(VII)之甲基碘在鹼的存在下反應，獲得式(I)化合物之粗產物。該式(I)化合物之粗產物係根據WO 03/095451之實例8的實驗程序及ChemMedChem 2009,4,853-865之類似描述藉由下列程序純化：以二氯甲烷/THF研製該粗產物、中間藉由過濾分離出經二氯甲烷/THF研製之產物、分離固體與甲醇一起沸騰、中間藉由過濾分離出與甲醇一起沸騰之固體、在活性碳的存在下將固體溶於二噁烷、二氯甲烷與甲醇之混合物中、經由矽藻土或塞利特矽藻土(Celite)藉由過濾去除活性碳、濃縮過濾溶液至乾、以甲醇研製濃縮至乾之固體、藉由過濾分離出經甲醇研製之固體並(WO 03/095451之實例8或ChemMedChem 2009,4,853-865中未描述，但客觀上需要)乾燥之。或者，可藉由製備型色層分析術(RP-HPLC)以不佳產率純化經濃縮乾燥之式(I)化合物之粗產物。Here, 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5 of formula (III) is initially cleaved by catalytic hydrogenation. -[(E)-phenyldiazenyl]pyrimidine-4,6-diamine, and 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3] of formula (IV) The resulting triamino compound is isolated as the 4-b]pyridin-3-yl]-4,5,6-pyrimidine triamine trihydrochloride salt. This trihydrochloride is then reacted with methyl chloroformate of formula (V) in a solvent pyridine to obtain 4,6-diamino-2-[1-(2-fluorobenzyl) of formula (VI). Methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate. Alternatively, ChemMedChem 2009, 4, 853-865 describes that the triamine compound is isolated as the trihydrochloride salt and then extracted with an aqueous solution of NaHCO 3 to yield HCl-free base, and the free base is combined with methyl chloroformate of formula (V) The reaction is carried out in a solvent pyridine to obtain a compound of the formula (VI). The compound of formula (VI) is then reacted with methyl iodide of formula (VII) in the presence of a base to provide the crude product of the compound of formula (I). The crude product of the compound of formula (I) is purified according to the experimental procedure of Example 8 of WO 03/095451 and a similar description by ChemMedChem 2009, 4, 853-865 by the following procedure: developing the crude product in dichloromethane/THF, intermediate borrowing The product developed by dichloromethane/THF is separated by filtration, the separated solid is boiled with methanol, the solid which is boiled with methanol is separated by filtration, and the solid is dissolved in dioxane and dichloro in the presence of activated carbon. In a mixture of methane and methanol, the activated carbon is removed by filtration through diatomaceous earth or Celite, the filtered solution is concentrated to dryness, and concentrated to dry solids by methanol, and methanol is separated by filtration. The solids developed were dried (as described in Example 8 of WO 03/095451 or ChemMedChem 2009, 4, 853-865, but objectively required). Alternatively, the concentrated dried compound of formula (I) can be purified by preparative chromatography (RP-HPLC) in poor yield.
此合成及純化具有許多極不利於大規模工業實行之缺點。特別係以式(IV)之三鹽酸鹽形式分離出該三胺基化合物時確實如此。氫氯酸之添加需要防酸工業設備，且該步驟之產率不令人滿意地僅為理論之59.3%(參見，例如WO 03/095451之實例8A)。式(IV)之三胺基化合物或對應HCl-游離鹼在溶劑吡啶中進行反應同樣係不利的。僅可藉由完全蒸發反應混合物分離出式(IV)化合物，其對工業規模係不利的(參見，例如WO 03/095451之實例5)。在相當大的規模下，此等步驟一般產生極大問題如反應以極大規模進行時，由於實質較長之熱應力而膠黏或熱分解。根據WO 03/095451之實例5的實驗程序藉於二乙基醚中沸騰的方式純化式(VI)產物亦有許多缺點。因為二乙基醚之高易燃性，此步驟僅可以更高的工業支出費用來實行。This synthesis and purification has many disadvantages that are highly detrimental to large-scale industrial implementation. This is especially true when the triamine based compound is isolated as the trihydrochloride salt of formula (IV). The addition of hydrochloric acid requires an acid-proof industrial equipment, and the yield of this step is unsatisfactorily only 59.3% of theory (see, for example, Example 8A of WO 03/095451). The reaction of the triamine-based compound of formula (IV) or the corresponding HCl-free base in the solvent pyridine is likewise disadvantageous. The compound of formula (IV) can only be isolated by complete evaporation of the reaction mixture, which is disadvantageous on an industrial scale (see, for example, example 5 of WO 03/095451). At considerable scales, these steps generally create significant problems such as when the reaction is carried out on a very large scale, due to substantial longer thermal stresses, which are either adhesive or thermally decomposed. Purification of the product of formula (VI) by boiling in diethyl ether according to the experimental procedure of Example 5 of WO 03/095451 also has a number of disadvantages. Because of the high flammability of diethyl ether, this step can only be carried out with higher industrial expenditures.
然而，特別不利的係式(I)粗產物之純化方法。一種有效的純化是使用作為醫藥活性化合物之必要條件。所述經由RP HPLC之純化，即色層分析純化為一種實驗室方法，以工業規模實行之係非常昂貴的。此外，僅為29%之所述式(I)粗產物之合成步驟及其純化的產率是非常低的。替代製備及純化方法非常複雜。其包括總計分離固體5次(濃縮至乾2次及過濾3次)而且如上已提及般以工業規模濃縮至乾係非常不利的。總之，當進行化學步驟時，分離固體5次之數目對以工業規模製備及純化醫藥活性化合物而言係極不利的。However, a particularly unfavorable method of purifying the crude product of formula (I). An effective purification is necessary for use as a pharmaceutically active compound. Purification via RP HPLC, i.e., chromatography, is a laboratory method that is very expensive to perform on an industrial scale. Furthermore, only 29% of the synthetic steps of the crude product of formula (I) and the yield of its purification are very low. Alternative preparation and purification methods are very complicated. It consists in total separation of the solids 5 times (concentration to dry 2 times and filtration 3 times) and it is very disadvantageous to concentrate to the dry system on an industrial scale as already mentioned. In summary, the number of times the solids are separated 5 times when performing the chemical step is extremely detrimental to the preparation and purification of pharmaceutically active compounds on an industrial scale.
因此，目標係提供一種安全且亦可有利地以工業規模進行並可以高產率及高純度和醫藥上可接受品質提供活性化合物之簡化方法。Accordingly, the object is to provide a simplified process which is safe and can also advantageously be carried out on an industrial scale and which provides active compounds in high yields and high purity and pharmaceutically acceptable qualities.
令人驚訝地，吾人現已發現一種製備式(I)之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯之方法，Surprisingly, we have now discovered a preparation of {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b of formula (I) a method of methyl pyridin-3-yl]pyrimidin-5-yl}methylaminocarbamate,
及其使用作為醫藥活性化合物之純化。此式(I)化合物之粗產物之新穎方法及純化在下列各點上係不同於迄今已知之方法：It is used as a purification of pharmaceutically active compounds. The novel method and purification of the crude product of the compound of formula (I) differs from the methods known to date in the following points:
-催化氫化式(III)化合物之後，以式(VIII)之游離鹼形式分離出該三胺基化合物而中間無形成鹽，- after catalytic hydrogenation of the compound of formula (III), the triamine compound is isolated as the free base of formula (VIII) without intermediate formation of a salt,
-式(VI)化合物之製備係利用氯甲酸甲酯或二碳酸二甲酯作為試劑以無吡啶製程進行，- the preparation of the compound of the formula (VI) is carried out in a pyridine-free process using methyl chloroformate or dimethyl dicarbonate as a reagent,
-式(VI)化合物係以本身已知方式利用甲基化試劑轉化成式(I)粗產物；使用作為醫藥活性化合物之式(I)粗產物之純化係經由化合物{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(1：1)，即式(II)化合物作為分離中間物或以混合物形式產生的方式進行- the compound of the formula (VI) is converted into the crude product of the formula (I) by means of a methylating agent in a manner known per se; the purification of the crude product of the formula (I) as a pharmaceutically active compound is carried out via the compound {4,6-diamine Methyl 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylcarbamate Dimethane (1:1), ie the compound of formula (II) is produced as a separation intermediate or as a mixture
憑藉此等差異，可克服迄今已知方法之缺點並以高產率及高純度和醫藥上可接受品質獲得活性化合物。By virtue of these differences, the disadvantages of the hitherto known methods can be overcome and the active compounds can be obtained in high yields and high purity and pharmaceutically acceptable qualities.
根據本發明用於製備式(I)化合物之方法及經由式(II)中間物之純化係詳細描述於下。The process for the preparation of the compounds of formula (I) according to the invention and the purification via intermediates of formula (II) are described in detail below.
催化氫化式(III)化合物Catalytic hydrogenation of compounds of formula (III)
根據本發明方法之第一步驟係始於催化氫化式(III)化合物。The first step of the process according to the invention begins with the catalytic hydrogenation of a compound of formula (III).
此可在雷尼(Raney)鎳或工業界慣用Pt/碳或Pd/碳觸媒的存在下進行。較佳係使用Pt/碳或Pd/碳。N,N-二甲基甲醯胺(DMF)、N,N-二甲基乙醯胺(DMA)或N-甲基-2-吡咯啶酮(NMP)，較佳係DMF係用作溶劑。This can be done in the presence of Raney nickel or the industry in conventional Pt/carbon or Pd/carbon catalysts. Pt/carbon or Pd/carbon is preferred. N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidone (NMP), preferably DMF is used as a solvent .
氫化條件係溫度40-80℃，較佳係50-70℃，壓力：2-90巴，較佳係5-70巴之氫氣，氫化時間：1-72小時，較佳係3-36小時。The hydrogenation conditions are a temperature of 40 to 80 ° C, preferably 50 to 70 ° C, a pressure of 2 to 90 bar, preferably 5 to 70 bar of hydrogen, and a hydrogenation time of 1 to 72 hours, preferably 3 to 36 hours.
藉由過濾去除觸媒之後，產物係由C1 -C4 -醇，較佳係甲醇或乙醇及/或水中沉澱。較佳係使用甲醇、異丙醇或乙醇與水之混合物。After removal of the catalyst by filtration, the product is precipitated from a C 1 -C 4 -alcohol, preferably methanol or ethanol and/or water. It is preferred to use methanol, isopropanol or a mixture of ethanol and water.
在本發明背景中，C1 -C4 -醇係具有1至4個碳原子之直鏈或分支醇。下列可者可以舉例方式或較佳實例方式提及：甲醇、乙醇、正丙醇、異丙醇、正丁醇及第三丁醇。此定義亦可應用於下文所用之C1 -C4 -醇。In the context of the present invention, a C 1 -C 4 -alcohol is a linear or branched alcohol having from 1 to 4 carbon atoms. The following may be mentioned by way of example or preferred examples: methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol. This definition can also be applied to the C 1 -C 4 -alcohol used hereinafter.
亦可在沉澱前先去除部分溶劑，根據本發明部分蒸餾去除0-80%，較佳係40-70%之溶劑。Part of the solvent may also be removed prior to precipitation, and from 0 to 80%, preferably from 40 to 70%, of the solvent is partially distilled according to the present invention.
依此方式獲得之濕潤產物係在較低壓力下乾燥：此獲得式(VIII)產物(相當於式(IV)之游離鹼)。The wet product obtained in this way is dried at a lower pressure: this gives the product of formula (VIII) (corresponding to the free base of formula (IV)).
然後式(VIII)產物例如與式(V)之氯甲酸甲酯以新穎的無吡啶製程進行反應以獲得式(VI)產物。The product of formula (VIII) is then reacted, for example, with methyl chloroformate of formula (V) in a novel pyridine-free process to obtain the product of formula (VI).
用於該反應之溶劑係C1 -C4 -醇，較佳係乙醇、甲醇、異丙醇，特佳係異丙醇。The solvent used in the reaction is a C 1 -C 4 -alcohol, preferably ethanol, methanol, isopropanol, and particularly preferably isopropanol.
以所用式(VIII)化合物計，氯甲酸甲酯之用量係1.0至3.0當量，較佳係從1.0至2.0當量。The methyl chloroformate is used in an amount of from 1.0 to 3.0 equivalents, preferably from 1.0 to 2.0 equivalents, based on the compound of the formula (VIII).
可能反應溫度係0-75℃，較佳係15-50℃。The reaction temperature may be 0-75 ° C, preferably 15-50 ° C.
反應期間，在反應混合物中形成形成式(IX)化合物之鹽酸鹽，即式(VI)產物之鹽酸鹽。此式(IX)產物係以含HCl產物形式分離出，並藉由鹼的添加***成式(VI)產物或其甚至可在分離前藉由鹼的添加***，因此直接分離出式(VI)產物。During the reaction, the hydrochloride salt of the compound of formula (IX), the hydrochloride salt of the product of formula (VI), is formed in the reaction mixture. The product of formula (IX) is isolated as a product containing HCl and is cleaved to form the product of formula (VI) by addition of a base or it may even be cleaved by addition of a base prior to separation, thereby directly separating formula (VI) product.
根據本發明較佳係在分離之前藉由鹼的添加***出式(IX)產物並直接分離出式(VI)之游離鹼。Preferably, according to the invention, the product of formula (IX) is cleaved by the addition of a base prior to separation and the free base of formula (VI) is isolated directly.
根據本發明，適合的鹼係所有pKB高於式(I)化合物之pKB之鹼。可能提及之實例係鹼金屬及鹼土金屬之氫氧化物、碳酸鹽及磷酸鹽、含氮有機鹼，如三烷基胺、胍或脒。可能提及之實例係氫氧化鋰、氫氧化鈉、氫氧化鉀、氫氧化銣、氫氧化銫、氫氧化鎂、氫氧化鈣、氫氧化鍶、氫氧化鋇、碳酸鋰、碳酸鈉、碳酸鉀、碳酸銣、碳酸銫、碳酸鎂、碳酸鈣、碳酸鍶及碳酸鋇、磷酸鈉及磷酸鉀、具有直鏈、環狀或分支C1 -C20 -烷基之三烷基胺及環狀或開環胍或脒。根據本發明較佳係三乙基胺、三丙基胺、二異丙基乙基胺、三丁基胺、二環己基乙基胺、環己基二甲基胺、環己基二乙基胺、三異辛基胺、三癸基胺、三-十二碳基胺、三-十六碳基胺、N-甲基嗎福啉、DBU、DBN、四甲基胍等。特佳係三乙基胺、三丁基胺、二異丙基乙基胺、N-甲基嗎福啉、DBU、DBN。According to the invention, suitable bases are all higher than the base of pKB of the compound of formula (I). Examples which may be mentioned are hydroxides, carbonates and phosphates of alkali metals and alkaline earth metals, nitrogen-containing organic bases such as trialkylamines, ruthenium or osmium. Examples which may be mentioned are lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate. , cesium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, cesium carbonate and cesium carbonate, sodium phosphate and potassium phosphate, trialkylamines having a linear, cyclic or branched C 1 -C 20 -alkyl group and cyclic or Open loop or 脒. Preferred according to the invention are triethylamine, tripropylamine, diisopropylethylamine, tributylamine, dicyclohexylethylamine, cyclohexyldimethylamine, cyclohexyldiethylamine, Triisooctylamine, tridecylamine, tri-dodecylamine, tri-hexadecylamine, N-methylmorpholine, DBU, DBN, tetramethylguanidine, and the like. Particularly preferred are triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN.
鹼之用量以所用式(V)之氯甲酸甲酯計係1.0至2.0當量，較佳係從1.0至1.5當量。The base is used in an amount of from 1.0 to 2.0 equivalents, preferably from 1.0 to 1.5 equivalents, based on the methyl chloroformate of the formula (V) used.
與鹼反應之可能反應溫度係0-100℃，較佳係15-70℃。The possible reaction temperature for the reaction with a base is 0-100 ° C, preferably 15-70 ° C.
式(VI)產物係以懸浮液形式存在，並藉由過濾分離之。以C1 -C4 -醇清洗之並在較低壓力下以慣用方式乾燥。The product of formula (VI) is in the form of a suspension and is isolated by filtration. It is washed with C 1 -C 4 -alcohol and dried in a conventional manner at a lower pressure.
在根據本發明另一種方法中，式(VIII)產物係與式(X)之二碳酸二甲酯反應以獲得式(VI)產物。此反應不需使用任何鹼，例如吡啶。In another process according to the invention, the product of formula (VIII) is reacted with dimethyl dicarbonate of formula (X) to obtain the product of formula (VI). This reaction does not require the use of any base such as pyridine.
用於此反應之溶劑係C1 -C4 -醇，較佳係乙醇、甲醇、異丙醇，特佳係異丙醇。The solvent system for the reaction of C 1 -C 4 - alcohol, preferably based ethanol, methanol, isopropanol, particularly preferably isopropanol system.
二碳酸二甲酯之用量以所用式(VIII)化合物計係1.0至3.0當量，較佳係從1.0至2.0當量。The amount of dimethyl dicarbonate is from 1.0 to 3.0 equivalents, preferably from 1.0 to 2.0 equivalents, based on the compound of the formula (VIII) used.
可能反應溫度係0-65℃，較佳係15-40℃。The reaction temperature may be 0-65 ° C, preferably 15-40 ° C.
式(VI)之產物沉澱並藉由過濾方式分離之。以C1 -C4 -醇清洗之並在較低壓力下以慣用方式乾燥。The product of formula (VI) is precipitated and isolated by filtration. It is washed with C 1 -C 4 -alcohol and dried in a conventional manner at a lower pressure.
與二碳酸二甲酯反應時，直接獲得式(VI)產物。因此不需另外添加鹼。When reacted with dimethyl dicarbonate, the product of formula (VI) is obtained directly. Therefore, no additional base is required.
兩種方法，即式(VIII)化合物與氯甲酸甲酯反應，並接著以鹼使式(IX)之鹽酸鹽***，或式(VIII)化合物與二碳酸二甲酯反應皆提供類似式(VI)產物之品質，因此源自這兩種方法之式(VI)產物皆可以相同方式用於進一步轉化成式(I)產物。Two methods, namely, reacting a compound of formula (VIII) with methyl chloroformate, and then splitting the hydrochloride of formula (IX) with a base, or reacting a compound of formula (VIII) with dimethyl dicarbonate provides a similar formula ( VI) The quality of the product, so that the products of formula (VI) derived from both processes can be used in the same manner for further conversion to the product of formula (I).
根據本發明偏好使用這兩種方法。Both methods are preferred for use in accordance with the present invention.
式(VI)化合物可形成溶劑合物或含溶劑固體形式，例如含甲醇、含乙醇或含異丙醇之固體形式。因此，當式(IX)之鹽酸鹽***成式(VI)產物，或以二碳酸二甲酯直接合成式(VI)產物時，可獲得使用作為溶劑之C1 -C4 -醇的溶劑合物。該溶劑合物在乾燥式(VI)產物期間亦係安定的，其不會完全分解且明顯無顯著溶劑殘留物，即，例如所提C1 -C4 -醇之殘留物，因此留在式(VI)產物中。另一方面，式(VI)產物並不需在太熱之溫度下乾燥，因為其在太高之溫度下可能分解形成副產物。The compound of formula (VI) can form a solvate or a solvent-containing solid form, such as a solid form containing methanol, ethanol or isopropanol. Thus, when the hydrochloride salt of the formula (IX) is cleaved to the product of the formula (VI) or the product of the formula (VI) is directly synthesized as dimethyl dicarbonate, a solvent using a C 1 -C 4 -alcohol as a solvent can be obtained. Compound. The solvate is also stable during the drying of the product of formula (VI), which does not completely decompose and is substantially free of significant solvent residues, ie, for example, residues of the proposed C 1 -C 4 -alcohol, thus remaining in the formula (VI) in the product. On the other hand, the product of formula (VI) does not need to be dried at too hot a temperature because it may decompose to form by-products at too high a temperature.
因此，根據本發明較佳係在不超過110°之產物溫度下，特佳係在不超過100°之產物溫度下乾燥以鹼***式(IX)之鹽酸鹽或以二碳酸二甲酯直接合成得到之式(VI)產物。在此，任何以溶劑合物形式存在之C1 -C4 -醇殘留物特佳係留在式(VI)產物中，並使用此形式之式(VI)產物製備式(II)中間物或式(I)產物。根據本發明，式(VI)產物極特佳係包含範圍從0至13%之異丙醇殘留溶劑。Therefore, it is preferred according to the invention to dry at a product temperature of not more than 110°, particularly preferably at a product temperature of not more than 100°, by alkali cleavage of the hydrochloride salt of formula (IX) or directly with dimethyl dicarbonate. The product of formula (VI) is synthesized. Here, any C 1 -C 4 -alcohol residue present in the form of a solvate is particularly preferably retained in the product of formula (VI), and the intermediate of formula (II) or formula is prepared using the product of formula (VI) in this form. (I) product. According to the invention, the product of formula (VI) is particularly preferred to comprise a residual solvent of isopropanol ranging from 0 to 13%.
依此方式獲得之式(VI)產物係以本身已知方式，例如根據WO 03/095451或ChemMedChem 2009,4,853-865中任一描述與甲基化劑Me-X反應以獲得包含高量式(I)化合物之粗產物。The product of the formula (VI) obtained in this way is reacted with the methylating agent Me-X in a manner known per se, for example according to any one of WO 03/095451 or ChemMedChem 2009, 4, 853-865, to obtain a high-volume formula ( I) The crude product of the compound.
根據本發明所用之甲基化劑Me-X係甲基碘、硫酸二甲酯、甲苯磺酸甲酯等並以甲基碘或硫酸二甲酯為佳。The methylating agent Me-X used in the present invention is methyl iodide, dimethyl sulfate, methyl toluenesulfonate or the like and preferably methyl iodide or dimethyl sulfate.
根據本發明，純化式(I)粗產物以使用作為醫藥活性化合物。為此，起初形成包含高量之式(II)化合物中間物之混合物。According to the invention, the crude product of formula (I) is purified for use as a pharmaceutically active compound. To this end, a mixture comprising a high amount of the intermediate of the compound of formula (II) is initially formed.
為此，令式(I)粗產物溶於DMSO中，若適當，在選自酮、醚、酯或醇之群之醫藥上可接受之簡單溶劑的存在下進行。此等可能提及之溶劑實例係：甲醇、乙醇、異丙醇、1-丁醇、2-丁醇、乙酸乙酯、乙酸異丙酯或乙酸丙酯、乙酸丁酯、第三丁基甲基醚、二異丙基醚、丙酮、甲基乙基酮、甲基異丁基酮等。較佳係乙醇、異丙醇、乙酸乙酯、異酸異丙酯、乙酸丁酯、甲基乙基酮、甲基異丁基酮；特佳係乙酸乙酯。亦可使用此等溶劑之混合物。To this end, the crude product of formula (I) is dissolved in DMSO, if appropriate in the presence of a pharmaceutically acceptable simple solvent selected from the group of ketones, ethers, esters or alcohols. Examples of such solvents that may be mentioned are: methanol, ethanol, isopropanol, 1-butanol, 2-butanol, ethyl acetate, isopropyl acetate or propyl acetate, butyl acetate, third butyl methyl ether , diisopropyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like. Preferred are ethanol, isopropanol, ethyl acetate, isopropyl isophthalate, butyl acetate, methyl ethyl ketone, methyl isobutyl ketone; Mixtures of such solvents can also be used.
以式(I)粗產物之使用量計，DMSO之添加量係100至750重量%，較佳係從150至500重量%。The amount of DMSO added is from 100 to 750% by weight, preferably from 150 to 500% by weight, based on the amount of the crude product of the formula (I).
若適當，以式(I)粗產物之使用量計，活性碳可以0.25至35重量%，較佳係從0.5至20重量%之量加入此混合物中。If appropriate, the activated carbon may be added to the mixture in an amount of from 0.25 to 35% by weight, preferably from 0.5 to 20% by weight, based on the amount of the crude product of the formula (I).
為形成溶液，將混合物加熱至40-120℃，較佳係50-100℃。To form a solution, the mixture is heated to 40-120 ° C, preferably 50-100 ° C.
為形成式(I)之醫藥上可接受產物必須過濾該溶液。該過濾必須獨立於是否添加活性碳地進行。This solution must be filtered to form a pharmaceutically acceptable product of formula (I). This filtration must be carried out independently of the addition of activated carbon.
除了DMSO之外，加入式(I)粗產物溶液中，即過濾前所用之醫藥上可接受溶劑之量，以DMSO計為25至200重量%，較佳係40至100重量%。In addition to DMSO, the amount of the pharmaceutically acceptable solvent used in the crude product of formula (I), i.e., before filtration, is from 25 to 200% by weight, preferably from 40 to 100% by weight, based on DMSO.
該過濾係趁熱進行，該溫度係40-120℃，較佳係50-100℃。The filtration is carried out thermally, and the temperature is 40-120 ° C, preferably 50-100 ° C.
過濾後，將醫藥上可接受溶劑，較佳係如上相同之溶劑加入熱濾液中。此導致式(II)產物結晶。After filtration, a pharmaceutically acceptable solvent, preferably the same solvent as above, is added to the hot filtrate. This results in the crystallization of the product of formula (II).
過濾前後，溶劑之總量以DMSO計係從200至1500重量%，較佳係400-1200重量%。The total amount of solvent before and after filtration is from 200 to 1500% by weight, preferably from 400 to 1200% by weight, based on DMSO.
添加溫度係30-110℃，較佳係35-90℃。The temperature is added at 30-110 ° C, preferably 35-90 ° C.
在分離含有高量式(II)化合物之固體之前，為使沉澱完全，將混合物冷卻至0-35℃之溫度範圍，較佳係冷卻至(例如)20-30℃之周遭溫度。To separate the solids containing the compound of formula (II), the mixture is cooled to a temperature in the range of 0-35 ° C, preferably to a temperature of, for example, 20-30 ° C, before the precipitation is complete.
利用慣用分離裝置如Nutsche管或離心機進行分離。為去除母液，分離期間以醫藥上可接受溶劑，較佳係如上相同之溶劑清洗分離物。Separation is carried out using a conventional separation device such as a Nutsche tube or a centrifuge. To remove the mother liquor, the isolate is washed with a pharmaceutically acceptable solvent, preferably a solvent as above, during the separation.
DMSO再溶解之後，該分離物包含高量之式(II)產物。此外，小量之式(I)產物通常亦可直接沉澱而不與DMSO形成溶劑合物。亦可能形成不同化學計量之溶劑合物或形成無固定化學計量之溶劑加成物。此外，DMSO亦可以未鍵結形式如附著殘留溶劑般存在。分離物中DMSO之含量通常係10至25重量%，較佳係12-17重量%。根據本發明，式(II)產物特佳係以此混合物形式形成並用於製備式(I)純化產物。After the DMSO is redissolved, the isolate contains a high amount of the product of formula (II). In addition, a small amount of the product of formula (I) can usually be precipitated directly without forming a solvate with DMSO. It is also possible to form solvates of different stoichiometry or to form solvent adducts without fixed stoichiometry. In addition, DMSO may also be present in an unbonded form such as a residual solvent. The content of DMSO in the isolate is usually from 10 to 25% by weight, preferably from 12 to 17% by weight. According to the invention, the product of formula (II) is preferably formed as a mixture and used to prepare a purified product of formula (I).
現可乾燥依此方式獲得之式(II)產物，或者以含有溶劑殘留物，即附著DMSO及沉澱溶劑之濕潤形式用於轉化成式(I)純化產物。The product of formula (II) obtained in this manner can now be dried or used in a wet form containing a solvent residue, i.e., attached DMSO and a precipitating solvent, for conversion to the purified product of formula (I).
式(II)化合物係新穎的。其可如下工作實例所述般以純形式製得並可經分析特徵化。The compounds of formula (II) are novel. It can be prepared in pure form as described in the working examples below and can be characterized by analysis.
對於醫藥用途，必須自式(II)產物或含有高量式(II)化合物之混合物中去除DMSO。For medical use, DMSO must be removed from the product of formula (II) or a mixture containing a high amount of the compound of formula (II).
為此，式(II)產物或含有高量式(II)產物之分離混合物係在選自酮、醚、酯或醇之群之醫藥上可接受溶劑中沸騰。此等可能提及之溶劑實例係：甲醇、乙醇、異丙醇、1-丁醇、2-丁醇、乙酸乙酯、乙酸異丙酯或乙酸丙酯、乙酸丁酯、第三丁基甲基醚、二異丙基醚、丙酮、甲基乙基酮、甲基異丁基酮等。較佳係乙醇、異丙醇、乙酸乙酯、乙酸異丙酯、乙酸丁酯、甲基乙基酮、甲基異丁基酮。亦可使用此等溶劑之混合物。特佳係使用乙酸乙酯或乙酸乙酯與乙醇之混合物。To this end, the product of formula (II) or a separation mixture containing a high amount of the product of formula (II) is boiled in a pharmaceutically acceptable solvent selected from the group of ketones, ethers, esters or alcohols. Examples of such solvents that may be mentioned are: methanol, ethanol, isopropanol, 1-butanol, 2-butanol, ethyl acetate, isopropyl acetate or propyl acetate, butyl acetate, third butyl methyl ether , diisopropyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like. Preferred are ethanol, isopropanol, ethyl acetate, isopropyl acetate, butyl acetate, methyl ethyl ketone, and methyl isobutyl ketone. Mixtures of such solvents can also be used. Particularly preferred is the use of ethyl acetate or a mixture of ethyl acetate and ethanol.
沸騰係在所提溶劑迴流下或若適當在稍高壓力下進行。該溫度係50-150℃，較佳係80-120℃。The boiling is carried out under reflux of the solvent or if suitably under slightly elevated pressure. The temperature is 50-150 ° C, preferably 80-120 ° C.
根據本發明方法相較於先前技術提供顯著優勢。特別令人驚訝地係中間無形成式(IV)化合物(三鹽酸鹽)，直接分離式(VIII)化合物(游離鹼)可使產率顯著增加，並同時使工業實施更加簡單(無防酸設備部件)。The method according to the invention provides significant advantages over the prior art. It is particularly surprising that the intermediate compound (IV) is not formed in the middle, and the direct isolation of the compound of formula (VIII) (free base) allows a significant increase in yield and at the same time makes industrial implementation simpler (no acid resistance) Equipment parts).
然後，式(VIII)化合物可以新穎無吡啶製程，以氯甲酸甲酯或二碳酸二甲酯轉化成式(VI)化合物。此等新穎製程非常簡單並可以最少之工業花費進行。反應後，式(VI)產物係以固體形式懸浮存在，並可藉由過濾無蒸發步驟地分離。所得產率非常高。The compound of formula (VIII) can then be converted to the compound of formula (VI) by methyl chloroformate or dimethyl dicarbonate in a novel pyridine-free process. These novel processes are very simple and can be carried out with minimal industrial expense. After the reaction, the product of the formula (VI) is suspended in a solid form and can be isolated by filtration without evaporation. The yield obtained is very high.
另外，令人驚訝地係用於醫藥用途之式(I)粗產物的純化特別可藉由再溶解於含DMSO溶劑混合物的方式進行，且該新穎式(II)化合物在此步驟中係以中間物形式，若適合在混合物中以高比例獲得。藉由此步驟，去除所有不純物，除了小量殘留物之外，因此在藉由簡單沸騰去除DMSO含量之後，留下高純度之式(I)固體。此固體一般係無色至極輕微黃色且分析純度(HPLC)明顯高於98重量%，其對醫藥用途而言係極為有利。In addition, the purification of the crude product of formula (I) surprisingly for medical use can be carried out in particular by redissolving in a solvent mixture containing DMSO, and the novel compound of formula (II) is intermediate in this step The form of the form, if suitable, is obtained in a high proportion in the mixture. By this step, all impurities are removed, except for a small amount of residue, thus leaving a high purity solid of formula (I) after removal of the DMSO content by simple boiling. This solid is generally colorless to very slightly yellow and analytical purity (HPLC) is significantly higher than 98% by weight, which is highly advantageous for medical use.
該製程在技術上可安全地進行並可以工業規模製造。其可有彈性地適合工廠之現有設備使用。在特佳具體實施例中，純化式(I)粗產物時，中間分離式(II)產物或含有高量式(II)化合物之混合物係在努茨(Nutsch)過濾乾燥器中進行。接著藉將溶劑直接加入努茨過濾乾燥器中並或無中間乾燥式(II)產物的方式自努茨過濾乾燥器中以中間物形式分離出式(II)產物中去除DMSO。此可避免公開操作式(II)產物之固體及相關污染風險。The process is technically safe and can be manufactured on an industrial scale. It can be flexibly adapted to existing equipment in the factory. In a particularly preferred embodiment, the intermediate separation of the product of formula (II) or the mixture containing a high amount of the compound of formula (II) is carried out in a Nutz filter drier. The DMSO is then removed from the product of formula (II) by intermediate addition of the solvent to the Nutz filter dryer and without intermediate drying of the product of formula (II) from the Nutz filter dryer. This avoids the exposure of the solids of the product of formula (II) and the associated contamination risks.
縮寫及首字母縮寫：Abbreviations and acronyms:
abs. 絕對Abs. absolutely
cat. 催化Cat. Catalytic
CI 化學電離(MS中)CI chemical ionization (in MS)
d 天d days
TLC 薄層色層分析術TLC thin layer chromatography
DMF 二甲基甲醯胺DMF dimethylformamide
DMSO 二甲基亞碸DMSO dimethyl sulfoxide
ee 鏡像異構物過量Ee mirror image isomer excess
EI 電子撞擊電離(MS中)EI electron impact ionization (in MS)
ent 鏡像異構物/鏡像異構物純度Ent mirror isomer/mirror isomer purity
eq 當量Eq equivalent
ESI 電噴灑離子化(MS中)ESI electrospray ionization (in MS)
GC-MS 氣相色層分析耦合質譜術GC-MS gas chromatography chromatography coupled mass spectrometry
重量% 重量百分率Weight% weight percentage
h 小時h hours
HPLC 高壓、高效液相色層分析術HPLC high pressure, high performance liquid chromatography
conc. 濃度Conc. concentration
LC-MS 液相色層分析耦合質譜術LC-MS liquid chromatography analysis coupled mass spectrometry
min 分鐘Min minute
MS 質譜術MS mass spectrometry
NMR 核磁共振光譜法NMR nuclear magnetic resonance spectroscopy
Ph 苯基Ph phenyl
Rf 滯留指數(TLC中)R f retention index (in TLC)
Rt 滯留時間(HPLC中)R t retention time (in HPLC)
RT 室溫RT room temperature
體積/體積 (溶液之)體積相對於體積之比例Volume/volume (solution) volume to volume ratio
aq 水性、水溶液Aq water, aqueous solution
下列實例說明本發明，但本發明不限於該等實例。The following examples illustrate the invention, but the invention is not limited to such examples.
實例1Example 1
2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺(VIII)之製備Preparation of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine (VIII)
在高壓釜中，使1100克之式(III)化合物懸浮於5.4公升之DMF中。加入44克之慣用水濕潤(約50%)5%Pd/碳觸媒，並在以氮氣惰化，並施加氫氣之後，於65巴之氫氣壓力及約60℃之內部溫度下氫化密封之高壓釜約18小時。冷卻至約25℃、排氣及惰性化之後，去除高壓釜之內容物，以650毫升之DMF清洗之。In an autoclave, 1100 g of the compound of formula (III) was suspended in 5.4 liters of DMF. Add 44 grams of conventionally wet water (about 50%) 5% Pd/carbon catalyst, and after hydrogenating with nitrogen and applying hydrogen, hydrogenate the sealed autoclave at a hydrogen pressure of 65 bar and an internal temperature of about 60 °C. About 18 hours. After cooling to about 25 ° C, venting and inerting, the contents of the autoclave were removed and washed with 650 ml of DMF.
合併依此相同方式進行之三種反應物，濾掉舊觸媒，以1.1公升之DMF清洗濾餅並在較低壓力下濃縮濾液至約其質量之三分之一。依序將8.25公升之甲醇及8.25公升之水計量送入約6.5公斤之殘留物中，令其完全結晶，使懸浮液冷卻至約5℃並濾掉固體和以甲醇/水(1：1體積)清洗之。在50℃及較低壓力下乾燥產物。重量為2415克，其相當於理論之91.8%。式(VIII)目標產物(游離鹼)之含量係>98面積%或>97重量%。最顯著之不純物係DMF(約0.8重量%)及水(約0.5重量%)。The three reactants were combined in the same manner, the old catalyst was filtered off, the filter cake was washed with 1.1 liters of DMF and the filtrate was concentrated to about one third of its mass at a lower pressure. 8.25 liters of methanol and 8.25 liters of water were sequentially metered into about 6.5 kg of residue, allowing it to crystallize completely, allowing the suspension to cool to about 5 ° C and filtering off the solids and methanol/water (1:1 volume) ) Cleaning it. The product was dried at 50 ° C and at a lower pressure. The weight is 2415 grams, which is equivalent to 91.8% of theory. The content of the target product (free base) of the formula (VIII) is >98 area% or >97% by weight. The most notable impurities were DMF (about 0.8% by weight) and water (about 0.5% by weight).
實例2Example 2
4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基胺基甲酸甲酯(VI)之製備Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate Preparation of (VI)
起初將3063克之式(VIII)化合物及30.7公升之工業級異丙醇裝入反應容器中。隨攪拌在20-25℃下計量裝入1641克之二碳酸二甲酯並在此溫度下攪拌混合物22小時。抽氣濾掉沉澱產物，以工業級異丙醇清洗之並在50℃及較低壓力下乾燥之。所得產物之重量係3748克或理論之105.9%。式(I)產物特別包含約4.7%實際上乾燥無法去除之異丙醇(部分以異丙醇溶劑合物存在)，且分析含量係89.5重量%(HPLC)。以此含量計，產率係理論之94.8%。Initially, 3063 grams of the compound of formula (VIII) and 30.7 liters of technical grade isopropanol were charged to the reaction vessel. With stirring, 1641 g of dimethyl dicarbonate was metered in at 20-25 ° C and the mixture was stirred at this temperature for 22 hours. The precipitated product was filtered off with suction, washed with technical grade isopropanol and dried at 50 ° C and a lower pressure. The weight of the resulting product is 3748 grams or 105.9% of theory. The product of formula (I) specifically comprises about 4.7% isopropanol (partially in the presence of isopropanol solvate) which is virtually insoluble and cannot be removed, and the analytical content is 89.5% by weight (HPLC). Based on this content, the yield is 94.8% of theory.
實例3Example 3
2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-4,5,6-嘧啶三胺(VIII)之製備Preparation of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine (VIII)
起初將300克之式(III)化合物、1600毫升之DMF及60克之水濕潤雷尼(Raney)鎳裝入高壓釜中並在惰性化後，在60℃之內部溫度及65巴之氫氣壓力下氫化約18小時。冷卻並排氣後，濾掉舊觸媒並以100毫升之DMF清洗之。在較低壓力下濃縮濾液至534.5克並在35-40℃下將750毫升之甲醇計量送入殘留物中，冷卻後，然後在0-5℃下將750毫升之水計量送入殘留物中。濾掉固體並在50℃及較低壓力下乾燥之。重量為219.7克或理論之91.8%。Initially 300 g of the compound of formula (III), 1600 ml of DMF and 60 g of water wet Raney nickel were charged into the autoclave and, after inertization, hydrogenated at an internal temperature of 60 ° C and a hydrogen pressure of 65 bar. About 18 hours. After cooling and venting, the old catalyst was filtered off and washed with 100 ml of DMF. The filtrate was concentrated to 534.5 g at a lower pressure and 750 ml of methanol was metered into the residue at 35-40 ° C. After cooling, 750 ml of water was metered into the residue at 0-5 ° C. . The solid was filtered off and dried at 50 ° C and a lower pressure. The weight is 219.7 grams or 91.8% of theory.
實例4Example 4
4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基胺基甲酸甲酯(VI)之製備Methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinylcarbamate Preparation of (VI)
起初將1.50公斤之式(VIII)化合物裝入反應容器中14.25公升之異丙醇裏，並隨攪拌將混合物加熱至35℃。在30分鐘內以穩定速率計量送入531克之氯甲酸甲酯，以750毫升之異丙醇清洗之並在35℃下攪拌混合物16小時。然後將混合物加熱至50℃並在50℃下隨著攪拌計量送入3.85公升之甲醇及606克之三乙基胺，以450毫升之甲醇清洗之。然後在50℃下攪拌混合物1小時，冷卻至RT並在RT下攪拌1小時。抽氣濾掉懸浮固體，各以3.0公升之異丙醇/甲醇(4：1)清洗2次，並以3.0公升之異丙醇清洗一次並抽乾之。在50℃下乾燥濕潤產物1小時，然後在100℃下真空乾燥箱中乾燥22小時。所得產物之重量係1.793公斤或理論之103.3%。式(VI)產物包含6.45%實際上乾燥無法去除之異丙醇(部分以異丙醇溶劑合物存在)，且分析含量係87.9重量%(HPLC)。以此含量計，產率係理論之90.8%。Initially 1.50 kg of the compound of formula (VIII) was charged to 14.25 liters of isopropanol in a reaction vessel and the mixture was heated to 35 ° C with stirring. 531 g of methyl chloroformate was metered in at a steady rate over 30 minutes, washed with 750 ml of isopropyl alcohol and the mixture was stirred at 35 ° C for 16 hours. The mixture was then heated to 50 ° C and fed with 3.85 liters of methanol and 606 grams of triethylamine at 50 ° C with stirring, and washed with 450 ml of methanol. The mixture was then stirred at 50 ° C for 1 hour, cooled to RT and stirred at RT for 1 hour. The suspended solids were filtered off with suction and washed twice with 3.0 liters of isopropanol/methanol (4:1) and once with 3.0 liters of isopropanol and drained. The wet product was dried at 50 ° C for 1 hour and then dried in a vacuum oven at 100 ° C for 22 hours. The weight of the obtained product was 1.793 kg or 103.3% of theory. The product of formula (VI) contained 6.45% isopropanol (partially in the presence of isopropanol solvate) which was virtually insoluble and could not be removed, and the analytical content was 87.9% by weight (HPLC). Based on this content, the yield is 90.8% of the theory.
對照實例5Comparative example 5
4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)之製備4,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl)amine Preparation of methyl carbamic acid (I)
(依本身已知方式根據WO 03/095451之實例8的第二程序甲基化)(Methylation according to the second procedure of Example 8 of WO 03/095451) in a manner known per se)
在20-25℃下，令1630克之式(VI)化合物懸浮於16.3公升之THF中。令懸浮液冷卻至-6至-4℃並計量送入3480克之1M雙(三甲基矽基)鈉醯胺溶液。攪拌混合物並計量送入596克之甲基碘。短暫攪拌混合物並令其緩慢溫熱至約5℃。在此溫度下攪拌混合物直到反應結束(約4小時)。以4.1公升之強度15%的氯化銨溶液清洗反應混合物4次。蒸發濃縮有機相至殘留物為約6.4公斤並將溫度調整至約25℃。濾掉沉澱固體，以總計3公升之THF清洗之並在50℃及較低壓力下乾燥之。此獲得1112克之式(I)粗產物。此相當於理論之75.2%的產率。1630 g of the compound of formula (VI) was suspended in 16.3 liters of THF at 20-25 °C. The suspension was cooled to -6 to -4 ° C and metered into 3480 grams of 1 M bis(trimethylsulfonyl)sodium decylamine solution. The mixture was stirred and metered into 596 grams of methyl iodide. The mixture was stirred briefly and allowed to slowly warm to about 5 °C. The mixture was stirred at this temperature until the end of the reaction (about 4 hours). The reaction mixture was washed 4 times with a 4.1 liter strength 15% ammonium chloride solution. The organic phase was concentrated by evaporation to a residue of about 6.4 kg and the temperature was adjusted to about 25 °C. The precipitated solid was filtered off, washed with a total of 3 liters of THF and dried at 50 ° C and a lower pressure. This gave 1112 g of the crude product of formula (I). This corresponds to a theoretical 75.2% yield.
實例6Example 6
由4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)與{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(II)組成並具高量之式(II)產物之混合物的製備From 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl) Methyl carbamic acid (I) and {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl] Preparation of a mixture of methyl pyrimidine-5-yl}methylaminocarbamate sulfinyl dimethane (II) and having a high amount of the product of formula (II)
在100℃下將9.0克已以類似對照實例5之方式製得之式(I)粗產物溶於16毫升之DMSO中。(在此實驗室實驗內免除此時必須進行以獲得醫學上可接受產物品質之過濾澄清化)。然後令混合物冷卻至75℃，加入110毫升之乙酸乙酯並令混合物緩慢冷卻至約25℃。濾掉沉澱固體，以總計28毫升之乙酸乙酯清洗，並在50℃及較低壓力下乾燥之。該重量係9.6克或理論之90.0%。9.0 g of the crude product of formula (I), which had been prepared in a similar manner to Comparative Example 5, was dissolved in 16 mL of DMSO at 100 °C. (In this laboratory experiment, filtration clarification must be performed at this time to obtain medically acceptable product quality). The mixture was then cooled to 75 ° C, 110 mL of ethyl acetate was added and the mixture was slowly cooled to about 25 °C. The precipitated solid was filtered off, washed with a total of 28 ml of ethyl acetate, and dried at 50 ° C and lower pressure. This weight is 9.6 grams or 90.0% of theory.
實例7Example 7
純化4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)之製備Purification of 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl (methyl) Preparation of methyl carbamate (I)
令上述實例6中所製得之所有式(II)產物量在135毫升之乙酸乙酯中迴流(約78℃)下攪拌1小時並冷卻至約25℃。抽氣濾掉固體，以總計36毫升之乙酸乙酯清洗之並在較低壓力下乾燥之。該重量係7.6克或理論之93.8%。產物之含量明顯高於98重量%(HPLC)。作為溶劑之乙酸乙酯係以約0.2%之量存在。DMSO含量係低於0.1%。All of the product of formula (II) prepared in the above Example 6 was stirred under reflux (about 78 ° C) in 135 ml of ethyl acetate for 1 hour and cooled to about 25 °C. The solid was filtered off with suction, washed with a total of 36 mL of ethyl acetate and dried at lower pressure. The weight is 7.6 grams or 93.8% of theory. The content of the product was significantly higher than 98% by weight (HPLC). Ethyl acetate as a solvent is present in an amount of about 0.2%. The DMSO content is less than 0.1%.
實例8Example 8
以中間分離出含有高量之{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(II)之濕潤產物的混合物製備純化4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]-5-嘧啶基(甲基)胺基甲酸甲酯(I)Separating a high amount of {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine Preparation of a mixture of -5-yl}methylaminocarbamate sulfinyl dimethane (II) as a wet product to prepare 4,6-diamino-2-[1-(2-fluorobenzyl)- Methyl 1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate (I)
在約96℃下將193.5克已以類似對照實例5之方式製得之式(I)粗產物溶於344毫升之DMSO及172毫升之乙酸乙酯中。然後加入19.4克之活性碳及172毫升之乙酸乙酯並攪拌熱混合物。然後過濾熱混合物以去除活性碳，以172毫升之乙酸乙酯清洗。將濾液之溫度調整至78℃並緩慢加入1850毫升之乙酸乙酯。在約2-3小時內，將混合物冷卻至約25℃並濾掉固體，以總計772公升之乙酸乙酯清洗之。令混合物中包含高量之式(II)化合物之濕潤產物懸浮於2900毫升之乙酸乙酯中，迴流加熱1小時並冷卻至約25℃。抽氣過濾固體，以總計774公升之乙酸乙酯清洗，並在50℃及較低壓力下乾燥之。所得重量係155.1克或起始物之80.2%。產物之含量明顯高於98重量%(HPLC)。關於溶劑，實際上僅乙酸乙酯及DMSO以小量存在。193.5 g of the crude product of formula (I), which had been prepared in a similar manner to that of Comparative Example 5, was dissolved in 344 ml of DMSO and 172 ml of ethyl acetate at about 96 °C. Then 19.4 g of activated carbon and 172 ml of ethyl acetate were added and the hot mixture was stirred. The hot mixture was then filtered to remove activated carbon and washed with 172 mL of ethyl acetate. The temperature of the filtrate was adjusted to 78 ° C and 1850 ml of ethyl acetate was slowly added. The mixture was cooled to about 25 ° C in about 2-3 hours and the solid was filtered off and washed with a total of 772 liters of ethyl acetate. The wet product containing the high amount of the compound of formula (II) in the mixture was suspended in 2900 ml of ethyl acetate, heated under reflux for 1 hour and cooled to about 25 °C. The solid was suction filtered, washed with a total of 774 liters of ethyl acetate and dried at 50 ° C and a lower pressure. The weight obtained was 155.1 g or 80.2% of the starting material. The content of the product was significantly higher than 98% by weight (HPLC). Regarding the solvent, only ethyl acetate and DMSO were actually present in small amounts.
實例9Example 9
{4,6-二胺基-2-[1-(2-氟苯甲基)-1H-吡唑并[3,4-b]吡啶-3-基]嘧啶-5-基}甲基胺基甲酸甲酯亞磺醯基二甲烷(II)之製備及分析特徵化{4,6-Diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}methylamine Preparation and analysis of methyl sulfinyl dimethane (II)
在約94℃下將14.8克已以類似對照實例5之方式製得之式(I)粗產物溶於28.9克之DMSO及11.85克之乙酸乙酯中。然後加入1.5克之活性碳Norit A-Supra及另一份11.85克之乙酸乙酯，迴流攪拌(88-90℃)混合物1小時，然後過濾熱混合物以去除活性碳。藉由溫熱至約78℃再度溶解部分已沉殿之固體，然後令該溶液緩慢冷卻。在RT下抽氣過濾沉澱固體，各以50毫升之乙酸乙酯清洗3次，並在乾燥箱中30℃下乾燥18小時。此獲得9.2克或理論之52.5%的式(II)化合物淡黃色結晶粉末。14.8 g of the crude product of formula (I), which had been prepared in a similar manner to Comparative Example 5, was dissolved in 28.9 g of DMSO and 11.85 g of ethyl acetate at about 94 °C. Then 1.5 g of activated carbon Norit A-Supra and another 11.85 g of ethyl acetate were added, and the mixture was stirred under reflux (88-90 ° C) for 1 hour, and then the hot mixture was filtered to remove activated carbon. The solid which has been dissolved in the chamber is again dissolved by warming to about 78 ° C, and then the solution is slowly cooled. The precipitated solid was suction-filtered at RT, washed three times with 50 ml of ethyl acetate, and dried in a dry box at 30 ° C for 18 hours. This gave 9.2 g or 52.5% of the compound of formula (II) as a pale yellow crystalline powder.
HPLC：99.90面積%(無考慮DMSO)HPLC: 99.90 area% (without considering DMSO)
DMSO(GC)：14.7重量%DMSO (GC): 14.7% by weight
1 H-NMR(400MHz，於DMF-d7 中)：d=2.59(s,約6H,DMSO之2 CH3 ),3.13(s,3H,N-CH3 ),3.58+3.67(兩個s,3H,於O-CH3 之受阻旋轉),5.91(s,2H,-CH2 -),6.53(s,4H,-NH2 ),7.05-7.40(m,5H,o-氟苯甲基取代基之4個芳族H及於吡啶環上吡啶氮之間位的1H),8.60(dd,吡啶環上吡啶氮之鄰位的1H),9.12(dd,吡啶環上吡啶氮之對位的1H)。 1 H-NMR (400 MHz in DMF-d 7 ): d = 2.59 (s, about 6H, DMSO 2 CH 3 ), 3.13 (s, 3H, N-CH 3 ), 3.58 + 3.67 (two s , 3H, hindered rotation at O-CH 3 ), 5.91 (s, 2H, -CH 2 -), 6.53 (s, 4H, -NH 2 ), 7.05-7.40 (m, 5H, o-fluorobenzyl) 4H of the substituent and 1H) of the position of the pyridyl nitrogen on the pyridine ring, 8.60 (dd, 1H ortho-position of the pyridyl nitrogen on the pyridine ring), 9.12 (dd, the para-position of the pyridyl nitrogen on the pyridine ring 1H).
元素分析：Elemental analysis:
Claims (4)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09177371 | 2009-11-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201200514A TW201200514A (en) | 2012-01-01 |
| TWI496781B true TWI496781B (en) | 2015-08-21 |
Family
ID=43536603
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW099140893A TWI496781B (en) | 2009-11-27 | 2010-11-26 | Process for preparing methyl {4,6-diamino-2-(1-(2-fluorobenzyl)-1h-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl}methylcarbamate and its purification for use as pharmaceutically active compound |
Country Status (43)
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20180203A1 (en) * | 2009-11-27 | 2018-01-31 | Adverio Pharma Gmbh | PROCEDURE FOR THE PREPARATION OF {4,6-DIAMINE-2- [1- (2-FLUOROBENZYL) -1H-PIRAZOLO [3,4-B] PYRIDIN-3-IL] PYRIMIDIN-5-IL} METHYL METHYLCARBAMATE AND ITS PURIFICATION FOR USE AS A PHARMACEUTICAL ACTIVE PRINCIPLE |
| PT3133070T (en) | 2009-11-27 | 2019-11-11 | Genzyme Corp | Eliglustat (genz 112638) as inhibitor of glucosylceramide synthase for use in a method of treating fabry's or gaucher's disease, the method comprising adjusting the individual therapeutical dose to the p-450 metabolism of the patient |
| DE102010021637A1 (en) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituted 5-fluoro-1H-pyrazolopyridines and their use |
| DE102010043380A1 (en) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Benzyl-substituted carbamates and their use |
| DE102010043379A1 (en) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Substituted 6-fluoro-1H-pyrazolo [4,3-b] pyridines and their use |
| UA111754C2 (en) | 2011-10-06 | 2016-06-10 | Байєр Фарма Акцієнгезелльшафт | SUBSTITUTED BENZILINDASOLS FOR THE APPLICATION OF BUB1-KINASE INHIBITORS FOR THE TREATMENT OF HYPERPROLIFERATIVE DISEASES |
| PL2896617T3 (en) | 2011-11-25 | 2017-07-31 | Adverio Pharma Gmbh | Method for producing substituted (z)-alpha-fluoro-beta-amino-acrylaldehydes |
| SG11201506211RA (en) | 2013-02-21 | 2015-09-29 | Adverio Pharma Gmbh | Forms of methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate |
| CN104327107A (en) | 2013-10-17 | 2015-02-04 | 广东东阳光药业有限公司 | Preparation method of fluoroquinolone antibiosis medicine |
| EP3194379A1 (en) | 2014-09-19 | 2017-07-26 | Bayer Pharma Aktiengesellschaft | Benzyl substituted indazoles as bub1 inhibitors |
| WO2016113415A1 (en) | 2015-01-16 | 2016-07-21 | Sandoz Ag | Process for the preparation of riociguat essentially free from genotoxic impurities |
| CN105367568B (en) * | 2015-11-18 | 2019-08-20 | 浙江京新药业股份有限公司 | A method of preparing the western croak of Leo |
| CN105294686B (en) * | 2015-11-30 | 2017-03-22 | 郑州大明药物科技有限公司 | Preparation method of riociguat |
| EP3389655A2 (en) | 2015-12-14 | 2018-10-24 | Ironwood Pharmaceuticals, Inc. | USE OF sGC STIMULATORS FOR THE TREATMENT OF GASTROINTESTINAL SPHINCTER DYSFUNCTION |
| WO2017103760A1 (en) * | 2015-12-15 | 2017-06-22 | Alembic Pharmaceuticals Limited | Novel polymorph of riociguat and its process for the preparation |
| CN108069960A (en) * | 2016-11-15 | 2018-05-25 | 江苏豪森药业集团有限公司 | The preparation method of the western croak intermediate of Leo |
| WO2018096550A1 (en) * | 2016-11-28 | 2018-05-31 | Msn Laboratories Private Limited, R&D Center | Process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof |
| WO2018111795A2 (en) | 2016-12-13 | 2018-06-21 | Ironwood Pharmaceuticals, Inc. | Use of sgc stimulators for the treatment of esophageal motility disorders |
| WO2018130226A1 (en) * | 2017-01-16 | 2018-07-19 | 苏州科睿思制药有限公司 | New crystal form of riociguat, preparation method and use thereof |
| MX2021000363A (en) | 2018-07-11 | 2021-04-29 | Cyclerion Therapeutics Inc | USE OF sGC STIMULATORS FOR THE TREATMENT OF MITOCHONRIAL DISORDERS. |
| CN111689961A (en) * | 2020-06-01 | 2020-09-22 | 江苏华阳制药有限公司 | Novel crystal form of lis ciguat and preparation method thereof |
| EP3925953A1 (en) * | 2020-06-16 | 2021-12-22 | Adverio Pharma GmbH | Process for preparing methyl {4,6-diamino-2-[5-fluoro-1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate |
| CN112316932B (en) * | 2020-11-13 | 2022-03-01 | 中国石油大学(北京) | Crude terephthalic acid hydrofining catalyst and preparation method and application thereof |
| CN112316968B (en) * | 2020-11-13 | 2022-03-01 | 中国石油大学(北京) | Crude terephthalic acid hydrofining catalyst and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060052397A1 (en) * | 2002-05-08 | 2006-03-09 | Bayer Healthcare Ag | Carbamate-substituted pyrazolopyridines |
Family Cites Families (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3950350A (en) * | 1974-12-27 | 1976-04-13 | Pfizer Inc. | Penam-dimethylsulfoxide complex |
| US4970210A (en) * | 1987-07-17 | 1990-11-13 | Abbott Laboratories | Triazinone lipoxygenase compounds |
| EP0409689B1 (en) * | 1989-07-18 | 1995-03-22 | Elf Atochem S.A. | A process for the purification of 1,1-bis(4-chlorophenyl)-2,2,2-trichloroethanol |
| GB9013750D0 (en) | 1990-06-20 | 1990-08-08 | Pfizer Ltd | Therapeutic agents |
| GB9301192D0 (en) | 1993-06-09 | 1993-06-09 | Trott Francis W | Flower shaped mechanised table |
| DE19642255A1 (en) | 1996-10-14 | 1998-04-16 | Bayer Ag | Use of 1-benzyl-3- (substituted-hetaryl) fused pyrazole derivatives |
| HUP0001115A3 (en) | 1996-10-14 | 2001-06-28 | Bayer Ag | Heterocyclylmethyl-substituted pyrazol derivatives, process for their preparation and pharmaceuticals containing the same |
| IL135462A0 (en) | 1997-11-12 | 2001-05-20 | Bayer Ag | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
| DE19834045A1 (en) | 1998-07-29 | 2000-02-03 | Bayer Ag | (4-Amino-5-ethylpyrimidin-2-yl) -1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b] pyridine |
| DE19846514A1 (en) | 1998-10-09 | 2000-04-20 | Bayer Ag | New arylmethyl and heterocyclylmethyl substituted heteroaryl-indazole derivatives useful in treatment of cardiovascular, ischemic and urogenital disorders |
| AR031176A1 (en) * | 2000-11-22 | 2003-09-10 | Bayer Ag | NEW DERIVATIVES OF PIRAZOLPIRIDINA SUBSTITUTED WITH PIRIDINE |
| DE10057754A1 (en) * | 2000-11-22 | 2002-05-23 | Bayer Ag | New cyclic sulfonamido-substituted pyrazolo (3,4-b) pyridine derivatives, are soluble guanylate cyclase stimulants useful e.g. for treating cardiovascular or central nervous system diseases, sexual dysfunction or inflammation |
| JP4295505B2 (en) | 2000-11-22 | 2009-07-15 | バイエル アクチェンゲゼルシャフト | New lactam substituted pyrazolopyridine derivatives |
| DE10057751A1 (en) * | 2000-11-22 | 2002-05-23 | Bayer Ag | New carbamate-substituted pyrazolo (3,4-b) pyridine derivatives, are soluble guanylate cyclase stimulants useful e.g. for treating cardiovascular or central nervous system diseases, sexual dysfunction or inflammation |
| DE10122894A1 (en) * | 2001-05-11 | 2002-11-14 | Bayer Ag | New pyrazolo(3,4-b)pyridin-3-yl)-5-pyrimidinyl sulfonates, are soluble guanyl cyclase stimulants useful e.g. for treating cardiovascular, thromboembolic or central nervous system diseases |
| DE10132416A1 (en) | 2001-07-04 | 2003-01-16 | Bayer Ag | New morpholine-bridged pyrazolopyridine derivatives |
| US6738631B1 (en) | 2002-05-06 | 2004-05-18 | Nokia, Inc. | Vision-guided model-based point-and-click interface for a wireless handheld device |
| JP4299573B2 (en) * | 2003-04-25 | 2009-07-22 | 東洋シヤッター株式会社 | Elevator door equipment |
| DE10222550A1 (en) | 2002-05-17 | 2003-11-27 | Bayer Ag | New 1-benzyl-3-(2-pyrimidinyl)-pyrazolo-(3,4-b)-pyridine derivatives are soluble guanylate cyclase stimulants, useful e.g. for treating cardiovascular or thromboembolic diseases or sexual dysfunction |
| DE10351903A1 (en) * | 2003-11-06 | 2005-06-09 | Bayer Healthcare Ag | New combination |
| KR200342343Y1 (en) | 2003-11-17 | 2004-02-18 | 김강철 | An amusement goods having the elasticity |
| KR20070008674A (en) * | 2004-04-01 | 2007-01-17 | 아스테라스 세이야쿠 가부시키가이샤 | Pyrazine derivatives and pharmaceutical use thereof as adenosine antagonists |
| TWI345568B (en) * | 2004-04-02 | 2011-07-21 | Mitsubishi Tanabe Pharma Corp | Tetrahydronaphthyridine derivatives and a process for preparing the same |
| DE102006043443A1 (en) | 2006-09-15 | 2008-03-27 | Bayer Healthcare Ag | Novel aza-bicyclic compounds and their use |
| DE102009004245A1 (en) | 2009-01-09 | 2010-07-15 | Bayer Schering Pharma Aktiengesellschaft | Novel fused, heteroatom-bridged pyrazole and imidazole derivatives and their use |
| PE20180203A1 (en) * | 2009-11-27 | 2018-01-31 | Adverio Pharma Gmbh | PROCEDURE FOR THE PREPARATION OF {4,6-DIAMINE-2- [1- (2-FLUOROBENZYL) -1H-PIRAZOLO [3,4-B] PYRIDIN-3-IL] PYRIMIDIN-5-IL} METHYL METHYLCARBAMATE AND ITS PURIFICATION FOR USE AS A PHARMACEUTICAL ACTIVE PRINCIPLE |
| UY33041A (en) * | 2009-11-27 | 2011-06-30 | Bayer Schering Pharma Aktienegesellschaft | PROCEDURE FOR THE PREPARATION OF {4,6-DIAMINO-2- [1- (2-FLUOROBENCIL) -1H-PIRAZOLO [3,4-B] PIRIDIN-3-IL] PIRIMIDIN-5-IL} CARBAMATO DE METTILO AND ITS PURIFICATION FOR USE AS A PHARMACEUTICAL ACTIVE PRINCIPLE |
| UY33040A (en) | 2009-11-27 | 2011-06-30 | Bayer Schering Pahrma Akitengesellschaft | NEW FORMS POLYMORPHES OF {4,6DIAMINO-2- [1- (2-FLUOROBENCIL-1H-PIRAZOL [3,4-B] PIRIDIN-3-IL] PIRIMIDIN-5-IL} METHYL CARBAMATE |
| DE102010021637A1 (en) | 2010-05-26 | 2011-12-01 | Bayer Schering Pharma Aktiengesellschaft | Substituted 5-fluoro-1H-pyrazolopyridines and their use |
| CN106977530A (en) | 2010-07-09 | 2017-07-25 | 拜耳知识产权有限责任公司 | Ring fusion pyrimidine and triazine and its be used for treat and/or prevention of cardiovascular disease purposes |
| DE102010040233A1 (en) | 2010-09-03 | 2012-03-08 | Bayer Schering Pharma Aktiengesellschaft | Bicyclic aza heterocycles and their use |
| DE102010043380A1 (en) | 2010-11-04 | 2012-05-10 | Bayer Schering Pharma Aktiengesellschaft | Benzyl-substituted carbamates and their use |
| ES2592267T3 (en) | 2011-05-06 | 2016-11-29 | Bayer Intellectual Property Gmbh | Imidazopyridines and substituted imidazopyridazines and their use |
| AU2012280246A1 (en) | 2011-07-06 | 2014-01-23 | Bayer Intellectual Property Gmbh | Heteroaryl-substituted pyrazolopyridines and use thereof as soluble guanylate cyclase stimulators |
| DE102012200360A1 (en) | 2012-01-11 | 2013-07-11 | Bayer Intellectual Property Gmbh | Substituted triazines and their use |
| JP6140738B2 (en) | 2012-03-06 | 2017-05-31 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ | Substituted azabicycles and uses thereof |
| SG11201505974VA (en) | 2013-03-01 | 2015-09-29 | Bayer Pharma AG | Trifluormethyl-substituted ring-fused pyrimidines and use thereof |
-
2010
- 2010-11-22 PE PE2017002307A patent/PE20180203A1/en unknown
- 2010-11-22 ES ES18178602T patent/ES2775902T3/en active Active
- 2010-11-22 KR KR1020177021646A patent/KR101861981B1/en active IP Right Grant
- 2010-11-22 JP JP2012540386A patent/JP5859451B2/en active Active
- 2010-11-22 TR TR2018/16146T patent/TR201816146T4/en unknown
- 2010-11-22 BR BR112012012617A patent/BR112012012617B8/en active IP Right Grant
- 2010-11-22 DK DK13151569.4T patent/DK2604608T3/en active
- 2010-11-22 MY MYPI2017001426A patent/MY180184A/en unknown
- 2010-11-22 PT PT14154762T patent/PT2733142T/en unknown
- 2010-11-22 PL PL14154762T patent/PL2733142T3/en unknown
- 2010-11-22 SI SI201031762T patent/SI2733142T1/en unknown
- 2010-11-22 CA CA2781799A patent/CA2781799C/en active Active
- 2010-11-22 DK DK18178602.1T patent/DK3415515T3/en active
- 2010-11-22 SI SI201031982T patent/SI3415515T1/en unknown
- 2010-11-22 CN CN201080053951.5A patent/CN102791707B/en active Active
- 2010-11-22 EA EA201590948A patent/EA031632B1/en not_active IP Right Cessation
- 2010-11-22 CA CA2936852A patent/CA2936852C/en active Active
- 2010-11-22 CN CN201410201245.0A patent/CN104059064B/en active Active
- 2010-11-22 LT LTEP14154762.0T patent/LT2733142T/en unknown
- 2010-11-22 ES ES10781686.0T patent/ES2524826T3/en active Active
- 2010-11-22 UA UAA201207918A patent/UA110779C2/en unknown
- 2010-11-22 EP EP18178602.1A patent/EP3415515B1/en active Active
- 2010-11-22 RS RS20200159A patent/RS59908B1/en unknown
- 2010-11-22 PL PL18178602T patent/PL3415515T3/en unknown
- 2010-11-22 EA EA201270636A patent/EA022813B1/en not_active IP Right Cessation
- 2010-11-22 WO PCT/EP2010/067949 patent/WO2011064171A2/en active Application Filing
- 2010-11-22 EP EP10781686.0A patent/EP2504334B1/en active Active
- 2010-11-22 EA EA201891964A patent/EA036422B1/en not_active IP Right Cessation
- 2010-11-22 PT PT181786021T patent/PT3415515T/en unknown
- 2010-11-22 PT PT107816860T patent/PT2504334E/en unknown
- 2010-11-22 SI SI201030773T patent/SI2504334T1/en unknown
- 2010-11-22 PL PL10781686T patent/PL2504334T3/en unknown
- 2010-11-22 BR BR122019002289-5A patent/BR122019002289B1/en active IP Right Grant
- 2010-11-22 DK DK10781686.0T patent/DK2504334T3/en active
- 2010-11-22 PE PE2012000706A patent/PE20121742A1/en active IP Right Grant
- 2010-11-22 BR BR122019002291A patent/BR122019002291B8/en active IP Right Grant
- 2010-11-22 AU AU2010323227A patent/AU2010323227B2/en active Active
- 2010-11-22 ES ES14154762.0T patent/ES2693746T3/en active Active
- 2010-11-22 HU HUE13151569A patent/HUE026778T2/en unknown
- 2010-11-22 EP EP14154762.0A patent/EP2733142B1/en active Active
- 2010-11-22 LT LTEP18178602.1T patent/LT3415515T/en unknown
- 2010-11-22 MX MX2012005938A patent/MX2012005938A/en active IP Right Grant
- 2010-11-22 NZ NZ715101A patent/NZ715101A/en unknown
- 2010-11-22 EP EP19214991.2A patent/EP3699180A1/en not_active Withdrawn
- 2010-11-22 ES ES13151569.4T patent/ES2553035T3/en active Active
- 2010-11-22 RS RSP20140579 patent/RS53585B1/en unknown
- 2010-11-22 HU HUE14154762A patent/HUE040328T2/en unknown
- 2010-11-22 EP EP13151569.4A patent/EP2604608B1/en active Active
- 2010-11-22 RS RS20150773A patent/RS54433B1/en unknown
- 2010-11-22 NZ NZ625983A patent/NZ625983A/en unknown
- 2010-11-22 DK DK14154762.0T patent/DK2733142T3/en active
- 2010-11-22 NZ NZ600199A patent/NZ600199A/en unknown
- 2010-11-22 RS RS20181208A patent/RS57790B1/en unknown
- 2010-11-22 CU CU2012000082A patent/CU24084B1/en active IP Right Grant
- 2010-11-22 PT PT131515694T patent/PT2604608E/en unknown
- 2010-11-22 PL PL13151569T patent/PL2604608T3/en unknown
- 2010-11-22 SI SI201031061T patent/SI2604608T1/en unknown
- 2010-11-22 KR KR1020127013611A patent/KR101766931B1/en active IP Right Grant
- 2010-11-22 MY MYPI2012002343A patent/MY173711A/en unknown
- 2010-11-23 UY UY0001033048A patent/UY33048A/en not_active Application Discontinuation
- 2010-11-24 AR ARP100104326A patent/AR079134A1/en active IP Right Grant
- 2010-11-25 JO JOP/2010/0415A patent/JO3107B1/en active
- 2010-11-26 TW TW099140893A patent/TWI496781B/en active
- 2010-11-29 US US12/955,510 patent/US8492544B2/en active Active
-
2012
- 2012-05-09 IL IL219683A patent/IL219683A/en active IP Right Grant
- 2012-05-23 CL CL2012001329A patent/CL2012001329A1/en unknown
- 2012-05-23 EC ECSP12011921 patent/ECSP12011921A/en unknown
- 2012-05-24 CO CO12085990A patent/CO6551708A2/en unknown
- 2012-05-24 TN TNP2012000257A patent/TN2012000257A1/en unknown
- 2012-05-24 GT GT201200158A patent/GT201200158A/en unknown
- 2012-05-24 CR CR20120280A patent/CR20120280A/en unknown
- 2012-05-24 DO DO2012000144A patent/DOP2012000144A/en unknown
- 2012-05-25 MA MA34924A patent/MA33783B1/en unknown
- 2012-06-21 ZA ZA2012/04610A patent/ZA201204610B/en unknown
-
2013
- 2013-05-16 HK HK13105844.2A patent/HK1178899A1/en unknown
- 2013-07-18 US US13/945,639 patent/US8853398B2/en active Active
-
2014
- 2014-06-04 US US14/295,922 patent/US10030014B2/en active Active
- 2014-11-03 SM SM201400164T patent/SMT201400164B/en unknown
- 2014-11-04 HR HRP20141073AT patent/HRP20141073T1/en unknown
- 2014-11-21 CY CY20141100969T patent/CY1115861T1/en unknown
-
2015
- 2015-03-18 HK HK15102784.9A patent/HK1202292A1/en unknown
- 2015-05-25 JP JP2015105630A patent/JP6133931B2/en active Active
- 2015-08-27 IL IL240878A patent/IL240878B/en active IP Right Grant
- 2015-10-14 AU AU2015243005A patent/AU2015243005B2/en active Active
- 2015-11-18 HR HRP20151243TT patent/HRP20151243T1/en unknown
-
2017
- 2017-01-04 JP JP2017000073A patent/JP6371871B2/en active Active
- 2017-02-02 JO JOP/2017/0032A patent/JO3651B1/en active
- 2017-02-02 JO JOP/2017/0033A patent/JO3650B1/en active
- 2017-04-05 IL IL251603A patent/IL251603B/en active IP Right Grant
- 2017-04-05 IL IL251601A patent/IL251601B/en active IP Right Grant
- 2017-05-05 AU AU2017203023A patent/AU2017203023B2/en active Active
-
2018
- 2018-03-08 EC ECIEPI201818453A patent/ECSP18018453A/en unknown
- 2018-06-05 US US16/000,382 patent/US10351562B2/en active Active
- 2018-07-06 JP JP2018128949A patent/JP6514398B2/en active Active
- 2018-10-30 HR HRP20181785TT patent/HRP20181785T1/en unknown
-
2019
- 2019-06-06 US US16/433,743 patent/US10570130B2/en active Active
-
2020
- 2020-03-10 HR HRP20200397TT patent/HRP20200397T1/en unknown
- 2020-03-17 DO DO2020000062A patent/DOP2020000062A/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060052397A1 (en) * | 2002-05-08 | 2006-03-09 | Bayer Healthcare Ag | Carbamate-substituted pyrazolopyridines |
Non-Patent Citations (1)
| Title |
|---|
| Schwoch Stefan et al. "2,3-Dihydrospiro[1H-4- and 5-azabenzimidazole -2,1’-cyclohexane](=Spiro[cyclohexane-1,2’(3’H)-1’H-imidazo[4,5-b]pyridine] and Spiro[cyclohexane-1,2’(3’H)-1’H-imidazo[4,5-c]pyridine]): Reaction with Nucleophiles." Helvetica Chimica Acta, 1994, Vol. 77, p. 2175-2190. * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI496781B (en) | Process for preparing methyl {4,6-diamino-2-(1-(2-fluorobenzyl)-1h-pyrazolo(3,4-b)pyridin-3-yl)pyrimidin-5-yl}methylcarbamate and its purification for use as pharmaceutically active compound | |
| US8501945B2 (en) | Process for preparing methyl {4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl}carbamate and its purification for use as pharmaceutically active compound |